The diversity and specificity of an immune response is embodied by the antigen-binding receptors on both B and T lymphocytes. The balance between proliferative expansion and programmed elimination of activated or autoreactive cells is also tightly regulated by these antigen receptors. Immunoglobulin D (IgD) and IgM are the two major antigen receptor isotypes expressed on the vast majority of peripheral B cells in humans and mice. While much evidence indicates that IgM is important in driving B-cell development, the contribution of IgD remains unclear, as are the roles of IgM and IgD in regulating humoral immune responses. Recently, we demonstrated that IgM and IgD have distinct roles in lymphoid homeostasis and in thymus-dependent humoral immune responses. These novel findings support a model in which signaling events through 8 or p. heavy chain differentially regulate B cell development and differentiation. This project will address several critical questions about the mechanisms how IgM and IgD receptors differentially condition cell survival/growth and cell death during B cell development using both IgM-deficient and IgD- deficient mouse models. Experiments will also investigate immune responses when either IgM or IgD is absent. Additional studies will probe the VDJ rearrangements and functions of B cells expressing multiple heavy chains in IgM +/- heterozygotes. The proposed studies will elucidate distinct functional features of IgM and IgD antigen receptors and illuminate mechanisms of B-cell homeostasis and B-cell immunity, which may lead to better understanding the molecular and cellular basis of immunodeficiency and autoimmune disorders.